Synthesis of 4,4′-dimethoxy-3,3′-bithiophene

Article abstract of DOI:10.1007/s11164-014-1747-x

Abstract Reaction between 3,3′-dibromothiophene and sodium methylate/methanol in the presence of KI/CuO afforded 3-bromo-4-methoxythiophene as a major product. It was transformed into 4,4′-dimethoxy-3,3′-bithiophene by using Pd(OAc)₂ as a catalyst and agarose as a ligand. The conditions of the reaction were mild with an acceptable yield of 20 %. The product was characterized by MS, ¹H NMR, and its spectra of UV-Vis and cyclic voltammetry were given. Graphical Abstract: 4,4′-dimethoxy-3,3′-bithiophene was synthesized from 3-bromo-4-methyloxy thiophene in the homogeneous system formed by water and agarose.[Figure not available: see fulltext.]

Full text of DOI:10.1007/s11164-014-1747-x

Res Chem Intermed
DOI 10.1007/s11164-014-1747-x
Synthesis of 4,40-dimethoxy-3,30-bithiophene
•
Hujin Zuo Rui Huang Qisong Zhang
•
•
•
Meijiang Li Chengyun Wang Yongjia Shen
•
Received: 18 March 2014 / Accepted: 12 June 2014
Ó Springer Science+Business Media Dordrecht 2014
Abstract Reaction between 3,30-dibromothiophene and sodium methylate/methanol in
the presence of KI/CuO afforded 3-bromo-4-methoxythiophene as a major product. It
was transformed into 4,40-dimethoxy-3,30-bithiophene by using Pd(OAc)2 as a catalyst
and agarose as a ligand. The conditions of the reaction were mild with an acceptable
1
yield of 20 %. The product was characterized by MS, H NMR, and its spectra of UV–
Vis and cyclic voltammetry were given.
Keywords Heterocycles ꢀ Steric ꢀ Agarose ꢀ UV/Vis spectroscopy ꢀ Cyclic
voltammetry
Introduction
Thiophene, as well as its derivatives, is one of the attractive compounds that contain S
element in the nature. They have widely been used in medicine, pesticides, and the
basic skeleton of functional materials [1–4]. Recently, they have developed drastically
in the field of optoelectronic materials due to their easy preparation, good thermal
stability, and outstanding optoelectronic properties [5, 6]. Among various derivatives
of the thiophene family, bithiophene is one of simplest building blocks to form
polythiophene, including 2,20-bithiophene and 3,30-bithiophene. Although both of
them are bithiophene, they are different from each other in both usage and synthetic
methods. 2,20-bithiophene is mainly used to synthesize organic electroluminescent
H. Zuo ꢀ R. Huang ꢀ Q. Zhang ꢀ C. Wang ꢀ Y. Shen (&)
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of
Science and Technology, Shanghai 200237, People’s Republic of China
e-mail: yjshen@ecust.edu.cn
M. Li
Key Lab of Organosilicon Chemistry and Material Technology of Ministry of Education, Hangzhou
Normal University, Hangzhou 310012, People’s Republic of China
123

H. Zuo et al.
materials, pharmaceuticals, photosensitivity pesticides, and dyes [7–12], while the
research of 3,30-bithiophene is focused on building blocks of photovoltaic materials
and others [13–15]. According to the references, 3,30-bithiophene was synthesized by
the reaction at -70 °C, with 3-bromothiophene and alkyl lithium as its reagents.
Apart from this, the reaction should be carried out with extreme scrutiny to avoid both
moisture and oxygen [16, 17]. Herein, our interest focused on finding an effective
method to couple a novel derivative of the thiophene family under mild conditions.
Experimental
General
3,30-Dibromothiophene, agarose, and Pd(OAc)2 were available from Energy
Chemical Co. in China. Other reagents and solvents were of commercial quality
and were distilled or dried when necessary by using standard procedures.
1H NMR spectra were obtained on BRUCK400 (internal standard was TMS).
Mass spectra were recorded using a HP-5898 spectrometer (EI). Absorption spectra
were measured with a UV-2450 UV–Vis spectrometer (Shimadzu Co.). Cyclic
voltammetry was carried out with CHI1040B (Shanghai Chenghua Instrumens Co.
Ltd., China).
Synthesis
Synthetic route of 4,40-dimethoxy-3,30-bithiophene 4 was showed as in Scheme 1.
Synthesis of 3-bromo-4-methoxy thiophene (3)
A mixture of 21.78 g 1 (0.09 mol), 150 cm3 methanol, 15 g sodium methylate,
3.6 g KI, and 3.6 g CuO was refluxed for 72 h. After removing methanol via
vacuum distillation, the residue was dissolved in ethyl acetate. The mixture was
filtered and the filtrate was washed by 100 cm3 9 3 saturated brine and dried over
anhydrous sodium sulfate. Ethyl acetate was then removed and the residue was
purified on silica column chromatography and 4.02 g (23.2 %) 3-bromo-4-methoxy
thiophene (3) and 1.44 g (11 %) 3,4-dimethoxythiophene(2) was obtained.
1
3-bromo-4-methoxy thiophene: H NMR (CDCl3, 400 MHz) ppm: d = 7.18 (d,
J = 3.5 Hz, 1H), 6.23 (d, J = 3.5 Hz, 1H), 3.86 (s, CH3O); MS (70 eV): m/
z = 192.0(M?).
1
3,4-dimethoxythiophene: H NMR (CDCl3, 400 MHz) ppm: d = 6.20 (s, 2H),
3.86 (s, 2CH3O); MS (70 eV): m/z = 144.0(M?).
Synthesis of 4,40-dimethoxy-3,30-bithiophene (4)
Agarose (0.75 g, 1.2 mmol) and 66 mg Pd(OAc)2 (0.3 mmol) were dissolved in
30 cm3 water. The solution was heated to 90 °C, then 2.895 g 3 (0.015 mol) and
0.9 g NaOH powder (2.25 mmol) were added in turn. The mixture was stirred for
123

Synthesis of 4,40-dimethoxy-3,30-bithiophene
OCH3
H3CO
S
Br
Br
2
CuO,KI
CH3ONa/CH3OH
S
S
1
H3CO
Br
H3CO
Pd(OAc)2 , Agarose,NaOH
H2O, 90 °C
OCH3
S
S
4
3
Scheme 1 Synthetic route of 4,40-dimethoxy-3,30-bithiophene 4
24 h at 90 °C. The reaction mixture was then cooled to room temperature. A dark
jelly-like solid formed was extracted with 10 cm3 9 3 Et2O. Evaporation of the
solvent, residue was purified on silica column chromatography, 0.678 g 4 (20 %)
1
was obtained. H NMR (CDCl3, 400 MHz) ppm: d = 7.78 (d, J = 3.4 Hz, 2H),
6.29 (d, J = 3.4 Hz, 2H), 3.90 (s, 2CH3O); MS (70 eV): m/z = 226.0(M?).
Results and discussion
Synthesis of 3-bromo-4-methoxythiophene (3)
According to the literatures [18, 19], the reaction between 3,4-dibromothiophene 1
and sodium methylate in the presence of CuO/KI could afford 3,4-dimethoxythioph-
ene 2 with a favorable yield of 76 %. However, we obtained a mixture of 3,4-
dimethoxythiophene 2 and 3-bromo-4-methoxythiophene 3, and 3 earned a higher
yield. With scrutiny of the experiment, we found that the sodium methylate used in
the literature was freshly prepared and the reaction was conducted under the
conditions extremely removing both moisture and oxygen. While, by contrast, we
executed the same reaction by using commercial sodium methylate in an opening
atmosphere. Perhaps the activity of commercial sodium methylate was lower than the
freshly prepared one, so that 3,4-dibromothiophene 1 could not be converted into 2
completely, giving more 3 in this reaction. Another method to synthesize 3 was
reported by Roncali and coworkers [20]. It was synthesized under microwaves and the
yield could reach 63 %. However, this method required both high temperature and
pressure. The rigorous condition might be dangerous and it is only applicable in
micro-reactions. By contrast, although our yield in 3 was not as high as they did, our
reaction condition was easy to be controlled and applicable for large amount reaction.
Synthesis of 4,40-dimethoxy-3,30-bithiophene (4)
There are two kinds of bithiophenes, 2,20-bithiophene and 3,30-bithiophene. Most
coupling reactions of halogenated thiophenes occur at 2,5-positions of the thiophene
ring, due to higher reactivity of the position affected by S atom, while the reactivity
123

H. Zuo et al.
of 3,4-positions in thiophene ring are much lower, i.e., more difficult to occur the
same reaction, especially in those thiophenes with a substituent in 3-position
because of the steric effect. In order to couple 3-bromo-4-methoxythiophene into
4,40dimethoxy-3,30-thiophene, we employed the Suzuki coupling reaction [21] with
some modifications. We conducted our reaction in water by using Pd(AcO)2 or
PdCl2 as catalyst and NaOH as base in the presence of agarose. Under the
conditions, 4,40dimethoxy-3,30-thiophene was successfully obtained. Agarose can
absorb water easily, thus a homogeneous gel system formed. In the system, the
catalyst and substrates incorporated into a large micelle. A large number of
hydroxyl groups in agarose could reduce Pd(II) to Pd(0) [21, 22]. In the case, the
agarose not only serves as carrier support but also as a reductive agent.
S
S
S
S
3,3'-bithiophene
2,2'-bithiophene
Although the reaction was successful, the yield of 4,40dimethoxy-3,30-thiophene
was lower than the same type of reaction, which happened in 2,5-positions of the
thiophene ring. Many tries were made to improve the yield, but they were all
unsuccessful. By increasing the reaction time to 24 h, the yield only reached 20 %.
Employing organic solvents, such as acetonitrile, ethyl acetate, and ethanol, to
replace water as solvent, the yield was much lower. 4,40dimethoxy-3,30-thiophene
could be detected by thin-layer chromatography, but could not be separated from the
system.
The simulated calculation by using DFT with Gaussian 03 indicated that the
conformation of 4,40dimethoxy-3,30-thiophene is a three-dimensional crossing
structure rather than a planar one (Fig. 1). We may conclude that a methoxy group
neighbored by bromine in 3-bromo-4-methoxythiophene could significantly
increases the steric effect, which makes the reaction yield as low as we mentioned
above.
UV absorption spectra
According to Fig. 2, both 3 and 4 displayed two absorption bands in methylene
chloride. The maximum absorption wavelengths were 259 nm for 3 and 278 nm for
4, respectively. By observing the maximum absorption, it was clear to find out the
wavelength of 4 was 19 nm bathochromic shift than 3, which was caused by the
extender conjugation degree after coupling. However, the bathochromic shift was
much less than we have expected due to a repulsion between the methoxy group as
well as carbon–carbon linking, resulting in un-planar thiophene rings (Fig. 1). Thus,
the delocalization degree of p electrons in 4 was reduced, and only a few
bathochromic shifts (19 nm) could be observed. The simulated calculation by using
DFT with Gaussian 03 also revealed that the energy gaps (DE) between LUMO and
HOMO were 5.76 eV for 3 and 5.05 eV for 4, similarly indicating a smaller band
gap in 4.
123

Synthesis of 4,40-dimethoxy-3,30-bithiophene
Fig. 1 Three-dimensional cross structure of 4,40-dimethoxy-3,30-bithiophene
0.16
0.14
0.12
0.10
0.08
0.06
0.04
0.02
0.00
-0.02
4
3
200
250
300
350
400
450
500
Wavelength(nm)
Fig. 2 UV–Vis absorption spectra of both 3 and 4 (1 9 10-5 mol dm-3) in CH2Cl2
Cyclic voltammetry
The CV curves of both 3 and 4 in methylene chloride are listed in Fig. 3. They
showed that the oxidation potentials were 1.88 V for 3 and 1.60 V for 4,
respectively, which implied that the oxidation of 4 was easier than 3. The reason for
this phenomenon could be discussed from the different substituted groups. In
compound 4, two methoxy groups which acted as electron donors could increase the
electron density of thiophene ring, leading a higher activity to be oxidized.
However, the bromo-substituted 3 owned a relatively lower electron density in
thiophene ring, due to the withdrawing effect of Br atom. Therefore, the
electrochemical oxidation of 4 is easier than 3.
123

H. Zuo et al.
0.0004
0.0002
0.0000
-0.0002
-0.0004
-0.0006
-0.0008
-0.0010
3
4
-2
-1
0
1
2
Potential/V
Fig. 3 The cyclic voltammogram of 3 (1 9 10-3 mol dm-3) and 4 (1 9 10-3 mol dm-3) in CH2Cl2
(scanning rate 100 mV S-1); platinum as the working and counter electrodes, Ag/AgCl electrode as the
reference electrode, n-Bu4NPF6 (0.1 mol dm-3) as the supporting electrolyte
Conclusions
In our work, we successfully synthesized 4,40-dimethoxy-3,30-bithiophene, a novel
member of the thiophene family, by an easy-going coupling reaction. The reaction
conditions were simple and mild rather than complicated and harsh, offering a new
method to take the place of the traditional oxygen-water free.
Acknowledgments This work was supported by the National Natural Science Foundation of China (No.
21076078).
References
1. S.A. Spinler, C. Rees, J. Manag. Care. Pharm. 15(5), 383 (2009)
´
ˇ´
´
2. Z. Puterova, A. Krutosıkova, D. Veghc, ARKIVOC 1, 209 (2010)
3. R.L. Jarvest, I.L. Pinto, S.M. Ashman, C.E. Dabrowski, C.E. Dabrowski, A.V. Femandez, L.J.
Jennings, P. Lavery, D.G. Tew, Bioorg. Med. Chem. Lett. 9, 443 (1999)
¨
4. A. Mishra, C.Q. Ma, P. Bauerle, Chem. Rev. 109, 1141 (2009)
5. D. Grebner, M. Helbig, S. Rentsch, J. Phys. Chem. 99, 16991 (1995)
6. H. Chosrovian, S. Rentsch, D. Grebner, D.U. Dahm, E. Birckner, H. Naarmann, Synth. Met. 60(1), 23
(1993)
7. Y. Tachibana, Y. Otsuka, K. Umekita, S. Kuwabata, Trans. Mater. Res. Soc. Jpn 33(1), 161 (2008)
8. H.H. Xu, S.F. Chiu, J. South China Agric Univ. 16(1), 127 (1995)
9. J.B. Hudson, L. Harris, A. Teeple, G.H.N. Towers, Antiviral Res. 20(1), 33 (1993)
10. Z.S. Jiang, H.H. Xu, S.Q. Wan, S.F. Chiu, S.Z. Su, Z.Z. Shang, Insect. Sci. 6(3), 253 (1999)
11. J.C. Henderson, Y. Kiya, G.R. Hutchison, H.D. Abrun˜a, J. Phys. Chem. C 112, 3989 (2008)
12. V. Fattori, M. Cocchi, P.D. Marco, G. Giro, G. Barbarella, G. Sotgiu, Synth. Met. 111–112, 83 (2000)
123

Synthesis of 4,40-dimethoxy-3,30-bithiophene
`
13. M. Benaglia, T. Benincori, P. Mussini, T. Pilati, S. Rizzo, F. Sannicolo, J. Org. Chem. 70, 7488
(2005)
14. H. Han, W.L. Zhao, J.S. Song, C.L. Li, H. Wang, J. Org. Chem. 78, 2726 (2013)
15. A. Meyer, E. Sigmund, F. Luppertz, G. Schnakenburg, I. Gadaczek, T. Bredow, S.S. Jester, S. Ho¨ger,
Beilstein J. Org. Chem. 6, 1180 (2010)
¨
16. S. Gronowitz, S. Hagen, Arkiv For Kemi 27(16), 153 (1966)
17. R. Satapathy, Y.H. Wu, H.C. Lin, Chem. Commun. 48, 5668 (2012)
18. S. Chen, B.Y. Lu, X.M. Duan, J.K. Xu, J. Polym. Sci. A Polym. Chem. 50, 1967 (2012)
19. K. Velauthamurtya, S.J. Higginsa, R.R.M. Gamini, H.M.N. Bandarab, M. Shimomurac, Electrochim.
Acta. 56, 326 (2010)
´
`
20. N. Hergue, C. Mallet, P. Frere, M. Allain, J. Roncali, Macromolecules 42, 5593 (2009)
21. H. Firouzabadi, N. Iranpoor, F. Kazemi, J. Mol. Catal. A Chem. 348, 94 (2011)
22. S. Ghosh, A. Saraswathi, S.S. Indi, S.L. Hoti, H.N. Vasan, Langmuir 28, 8550 (2012)
123